PD-L1 up-regulation in melanoma increases disease aggressiveness and is mediated through miR-17-5p

Abstract

PD-L1 is expressed by a subset of patients with metastatic melanoma (MM) with an unfavorable outcome. Its expression is increased in cells resistant to BRAF or MEK inhibitors (BRAFi or MEKi). However, the function and regulation of expression of PD-L1 remain incompletely understood.After generating BRAFi- and MEKi-resistant cell lines, we observed marked up-regulation of PD-L1 expression. These cells were characterized by a common gene expression profile with up-regulation of genes involved in cell movement. Consistently, in vitro they showed significantly increased invasive properties. This phenotype was controlled in part by PD-L1, as determined after silencing the molecule. Up-regulation of PD-L1 was due to post-transcriptional events controlled by miR-17-5p, which showed an inverse correlation with PD-L1 mRNA. Direct binding between miR-17-5p and the 3’-UTR of PD-L1 mRNA was demonstrated using luciferase reporter assays.In a cohort of 80 BRAF-mutated MM patients treated with BRAFi or MEKi, constitutive expression of PD-L1 in the absence of immune infiltrate, defined the patient subset with the worst prognosis. Furthermore, PD-L1 expression increased in tissue biopsies after the metastatic lesions became resistant to BRAFi or MEKi. Lastly, plasmatic miR-17-5p levels were higher in patients with PD-L1+ than PD-L1- lesions.In conclusion, our findings indicate that PD-L1 expression induces a more aggressive behavior in melanoma cells. We also show that PD-L1 up-regulation in BRAFi or MEKi-resistant cells is partly due to post-transcriptional mechanisms that involve miR-17-5p, suggesting that miR-17-5p may be used as a marker of PD-L1 expression by metastatic lesions and ultimately a predictor of responses to BRAFi or MEKi.

Noncoding RNAs in cancer immunity: functions, regulatory mechanisms, and clinical application

“…In addition, miR-34a [110,111], miR-138-5p [112], miR-25-93-106b [113], and miR-217 [114] have been demonstrated to inhibit the expression of PD-L1, thereby increasing antitumor immunity and inhibiting multiple metastatic traits. In contrast, modulation of miR-17-5p [115] and miR-197 [116] has been shown to be crucial for protumor function. Other types of ncRNAs, including lncRNAs and circRNAs, have also been reported to be involved in the regulation of the PD-1/PD-L1 pathway.…”

“…For example, recent studies reveal that blockade of miR-23a restored adoptive T cell transfer therapy providing new insights into improvement of immunotherapy efficacy [106]. Meanwhile, ncRNAs involved in the regulation of the PD-1/PD-L1 pathway may have a major role in limiting effective cancer immunity [110][111][112][113][114][115][116][117].…”

miRNAs as Key Players in the Management of Cutaneous Melanoma

“…PD-L1 overexpressing melanoma have been shown to be resistant BRAFi and MEKi. Audrito et al [63] demonstrated that miR-17-5p binds to PD-L1, suggesting its role in the resistance to targeted therapies.…”

Immuno-Oncology Biomarkers for Personalized Immunotherapy in Breast Cancer

“…Hence, miRNAs that specifically control one-target checkpoints are favored in biomarker development. Various miRNAs such as miR-34a, miR-17-5p, miR-15b, miR-193a-3p, miR-197miR-200c showed correlation with expression of PD-L1 in tumor tissues as well as in sera or plasmas, and purposed to have predictive values in ICBs therapy of different cancers (Chen et al, 2014;Cortez et al, 2016;Ahn et al, 2017;Audrito et al, 2017;Kao et al, 2017;Fan et al, 2019). In breast cancer, a panel of thirteen miRNAs has been identified that directly target and down-regulate B7-H3.…”